Dynamic m6A modification regulates local translation of mRNA in axons

Abstract

N 6-methyladenosine (m6A) is a reversible modification in mRNA and has been shown to regulate processing, translation and decay of mRNA. However, the roles of m6A modification in neuronal development are still not known. Here, we found that the m6A eraser FTO is enriched in axons and can be locally translated. Axon-specific inhibition of FTO by rhein, or compartmentalized siRNA knockdown of Fto in axons led to increases of m6A levels. GAP-43 mRNA is modified by m6A and is a substrate of FTO in axons. Loss-of-function of this non-nuclear pool of FTO resulted in increased m6A modification and decreased local translation of axonal GAP-43 mRNA, which eventually repressed axon elongation. Mutation of a predicted m6A site in GAP-43 mRNA eliminated its m6A modification and exempted regulation of its local translation by axonal FTO. This work showed an example of dynamic internal m6A demethylation of non-nuclear localized mRNA by the demethylase FTO. Regulation of m6A modification of axonal mRNA by axonal FTO might be a general mechanism to control their local translation in neuronal development.

The m6A‐epitranscriptomic signature in neurobiology: from neurodevelopment to brain plasticity

“…Most of the m6A target genes fall into the functional terms 'synapse' and 'cell junction', as well as surface receptor pathways, all of which maintain the integrity and functionality of tripartite synapses, which comprise the pre-and post-synaptic terminals, and their interaction with astrocytes. The localization of m6A in axons and its role in axonal growth have also been reported (Yu et al 2018). The transcript encoding an axonal elongation factor, Gap-43, was identified as an mRNA target the local translation of which is negatively regulated by m6A and can be modulated by FTO in the axon.…”

“…The localization of m6A in axons and its role in axonal growth have also been reported (Yu et al . ). The transcript encoding an axonal elongation factor, Gap‐43 , was identified as an mRNA target the local translation of which is negatively regulated by m6A and can be modulated by FTO in the axon.…”

“…Interestingly, one of the m6A‐modified transcripts, Gap43 , which plays an important role in axonal growth (Yu et al . ), is a well‐known target of HuD (Bolognani et al . ).…”

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

“…It is worth noting that this study demonstrates that overexpression of miR‐24‐2 in human hepatoma cell line Hep3B promotes the expression of N6‐adenine methyltransferase METTL3 and thereby increases methylation modification (m6A) on N6‐adenosine from specific RNA. Indeed, m6A is one of the major modifications of RNA that regulates the processing, translation and decay of RNA, which plays a key role in RNA metabolism and function . Furthermore, m6A, which is mainly catalysed by METTL3, regulates RNA stability mainly through m6A‐specific binding proteins which in turn determines cellular fate and function .…”

“…Indeed, m6A is one of the major modifications of RNA that regulates the processing, translation and decay of RNA, which plays a key role in RNA metabolism and function. 51,52 Furthermore, m6A, which is mainly catalysed by METTL3, regulates RNA stability mainly through m6A-specific binding proteins which in turn determines cellular fate and function. 53,54 In particular, N 6methyladenosine (m 6 A) has been shown recently to play essential roles in various bioprocesses.…”